{"doi":"10.1001/jamaneurol.2021.1858","title":"Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease","abstract":"Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, Setting, and Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main Outcomes and Measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. Conclusions and Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.","journal":"JAMA Neurology","year":2021,"id":145763,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":317,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9677,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":226048,"name":"Ruben Smith","orcid":"0000-0001-7147-0112","position":1,"is_corresponding":false},{"id":230942,"name":"Niklas Mattsson","orcid":"0000-0002-8885-7724","position":2,"is_corresponding":false},{"id":332619,"name":"Colin Groot","orcid":"0000-0002-5802-6946","position":3,"is_corresponding":false},{"id":272068,"name":"Antoine Leuzy","orcid":"0000-0003-4542-7879","position":4,"is_corresponding":false},{"id":229338,"name":"Olof Strandberg","orcid":null,"position":5,"is_corresponding":false},{"id":230950,"name":"Sebastian Palmqvist","orcid":"0000-0002-9267-1930","position":6,"is_corresponding":false},{"id":95158,"name":"Tomas Olsson","orcid":"0000-0002-2938-1877","position":7,"is_corresponding":false},{"id":618760,"name":"Jonas Jögi","orcid":"0000-0002-5299-3628","position":8,"is_corresponding":false},{"id":619776,"name":"Erik Stormrud","orcid":null,"position":9,"is_corresponding":false},{"id":618761,"name":"Hanna Cho","orcid":"0000-0001-5936-1546","position":10,"is_corresponding":false},{"id":618762,"name":"Young Hoon Ryu","orcid":"0000-0002-9000-5563","position":11,"is_corresponding":false},{"id":63640,"name":"Jae Yong Choi","orcid":"0000-0003-1901-8238","position":12,"is_corresponding":false},{"id":253908,"name":"Adam L. Boxer","orcid":"0000-0002-1215-5064","position":13,"is_corresponding":false},{"id":260467,"name":"Maria Luisa Gorno‐Tempini","orcid":"0000-0002-7426-7782","position":14,"is_corresponding":false},{"id":58513,"name":"Bruce L. Miller","orcid":"0000-0002-2152-4220","position":15,"is_corresponding":false},{"id":347739,"name":"David N. Soleimani‐Meigooni","orcid":"0000-0003-4197-3039","position":16,"is_corresponding":false},{"id":275271,"name":"Leonardo Iaccarino","orcid":"0000-0003-0053-9519","position":17,"is_corresponding":false},{"id":260103,"name":"Renaud La Joie","orcid":"0000-0003-2581-8100","position":18,"is_corresponding":false},{"id":246340,"name":"Suzanne L. Baker","orcid":"0000-0003-0209-3127","position":19,"is_corresponding":false},{"id":618763,"name":"Edilio Borroni","orcid":"0000-0001-9689-7374","position":20,"is_corresponding":false},{"id":619777,"name":"Gregory Klein","orcid":"0000-0001-7571-8912","position":21,"is_corresponding":false},{"id":618764,"name":"Michael J. Pontecorvo","orcid":"0000-0002-8419-7589","position":22,"is_corresponding":false},{"id":618765,"name":"Michael D. Devous","orcid":"0000-0002-6871-0063","position":23,"is_corresponding":false},{"id":51717,"name":"William J. Jagust","orcid":"0000-0002-4458-113X","position":24,"is_corresponding":false},{"id":342693,"name":"Chul Hyoung Lyoo","orcid":"0000-0003-2231-672X","position":25,"is_corresponding":false},{"id":230947,"name":"Gil D. Rabinovici","orcid":"0000-0002-3626-4265","position":26,"is_corresponding":false},{"id":65584,"name":"Oskar Hansson","orcid":"0000-0001-8467-7286","position":27,"is_corresponding":false},{"id":230944,"name":"Rik Ossenkoppele","orcid":"0000-0003-1584-7477","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:42:12.871665Z","pmid":"34180956","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}